Discovery of VU2957 (Valiglurax): An mGlu                         4                          Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease

Joseph D. Panarese; Darren W. Engers; Yong Jin Wu; Joanne J. Bronson; John E. Macor; Aspen Chun; Alice L. Rodriguez; Andrew S. Felts; Julie L. Engers; Matthew T. Loch; Kyle A. Emmitte; Arlindo L. Castelhano; Michael J. Kates; Michael A. Nader; Carrie K. Jones; Anna L. Blobaum; P. Jeffrey Conn; Colleen M. Niswender; Corey R. Hopkins; Craig W. Lindsley

doi:10.1021/acsmedchemlett.8b00426

Discovery of VU2957 (Valiglurax): An mGlu ₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease

Joseph D. Panarese, Darren W. Engers, Yong Jin Wu, Joanne J. Bronson, John E. Macor, Aspen Chun, Alice L. Rodriguez, Andrew S. Felts, Julie L. Engers, Matthew T. Loch, Kyle A. Emmitte, Arlindo L. Castelhano, Michael J. Kates, Michael A. Nader, Carrie K. Jones, Anna L. Blobaum, P. Jeffrey Conn, Colleen M. Niswender, Corey R. Hopkins, Craig W. Lindsley

Research output: Contribution to journal › Article

5 Scopus citations

Abstract

Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu ₄ PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease.

Original language	English
Pages (from-to)	255-260
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	3
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00426
State	Published - 14 Mar 2019

Keywords

Parkinson's disease
Positive allosteric modulator (PAM)
VU2957
metabotropic glutamate receptor 4 (mGlu )

Access to Document

10.1021/acsmedchemlett.8b00426

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Panarese, J. D., Engers, D. W., Wu, Y. J., Bronson, J. J., Macor, J. E., Chun, A., Rodriguez, A. L., Felts, A. S., Engers, J. L., Loch, M. T., Emmitte, K. A., Castelhano, A. L., Kates, M. J., Nader, M. A., Jones, C. K., Blobaum, A. L., Conn, P. J., Niswender, C. M., Hopkins, C. R., & Lindsley, C. W. (2019). Discovery of VU2957 (Valiglurax): An mGlu ₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease. ACS Medicinal Chemistry Letters, 10(3), 255-260. https://doi.org/10.1021/acsmedchemlett.8b00426

Panarese, Joseph D. ; Engers, Darren W. ; Wu, Yong Jin ; Bronson, Joanne J. ; Macor, John E. ; Chun, Aspen ; Rodriguez, Alice L. ; Felts, Andrew S. ; Engers, Julie L. ; Loch, Matthew T. ; Emmitte, Kyle A. ; Castelhano, Arlindo L. ; Kates, Michael J. ; Nader, Michael A. ; Jones, Carrie K. ; Blobaum, Anna L. ; Conn, P. Jeffrey ; Niswender, Colleen M. ; Hopkins, Corey R. ; Lindsley, Craig W. / Discovery of VU2957 (Valiglurax) : An mGlu ₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease. In: ACS Medicinal Chemistry Letters. 2019 ; Vol. 10, No. 3. pp. 255-260.

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title = "Discovery of VU2957 (Valiglurax): An mGlu 4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease",

abstract = " Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu 4 PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease. ",

keywords = "Parkinson's disease, Positive allosteric modulator (PAM), VU2957, metabotropic glutamate receptor 4 (mGlu )",

author = "Panarese, {Joseph D.} and Engers, {Darren W.} and Wu, {Yong Jin} and Bronson, {Joanne J.} and Macor, {John E.} and Aspen Chun and Rodriguez, {Alice L.} and Felts, {Andrew S.} and Engers, {Julie L.} and Loch, {Matthew T.} and Emmitte, {Kyle A.} and Castelhano, {Arlindo L.} and Kates, {Michael J.} and Nader, {Michael A.} and Jones, {Carrie K.} and Blobaum, {Anna L.} and Conn, {P. Jeffrey} and Niswender, {Colleen M.} and Hopkins, {Corey R.} and Lindsley, {Craig W.}",

year = "2019",

month = mar,

day = "14",

doi = "10.1021/acsmedchemlett.8b00426",

language = "English",

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journal = "ACS Medicinal Chemistry Letters",

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Panarese, JD, Engers, DW, Wu, YJ, Bronson, JJ, Macor, JE, Chun, A, Rodriguez, AL, Felts, AS, Engers, JL, Loch, MT, Emmitte, KA, Castelhano, AL, Kates, MJ, Nader, MA, Jones, CK, Blobaum, AL, Conn, PJ, Niswender, CM, Hopkins, CR & Lindsley, CW 2019, 'Discovery of VU2957 (Valiglurax): An mGlu ₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease', ACS Medicinal Chemistry Letters, vol. 10, no. 3, pp. 255-260. https://doi.org/10.1021/acsmedchemlett.8b00426

Discovery of VU2957 (Valiglurax) : An mGlu ₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease. / Panarese, Joseph D.; Engers, Darren W.; Wu, Yong Jin; Bronson, Joanne J.; Macor, John E.; Chun, Aspen; Rodriguez, Alice L.; Felts, Andrew S.; Engers, Julie L.; Loch, Matthew T.; Emmitte, Kyle A.; Castelhano, Arlindo L.; Kates, Michael J.; Nader, Michael A.; Jones, Carrie K.; Blobaum, Anna L.; Conn, P. Jeffrey; Niswender, Colleen M.; Hopkins, Corey R.; Lindsley, Craig W.

In: ACS Medicinal Chemistry Letters, Vol. 10, No. 3, 14.03.2019, p. 255-260.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Discovery of VU2957 (Valiglurax)

T2 - An mGlu 4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease

AU - Panarese, Joseph D.

AU - Engers, Darren W.

AU - Wu, Yong Jin

AU - Bronson, Joanne J.

AU - Macor, John E.

AU - Chun, Aspen

AU - Rodriguez, Alice L.

AU - Felts, Andrew S.

AU - Engers, Julie L.

AU - Loch, Matthew T.

AU - Emmitte, Kyle A.

AU - Castelhano, Arlindo L.

AU - Kates, Michael J.

AU - Nader, Michael A.

AU - Jones, Carrie K.

AU - Blobaum, Anna L.

AU - Conn, P. Jeffrey

AU - Niswender, Colleen M.

AU - Hopkins, Corey R.

AU - Lindsley, Craig W.

PY - 2019/3/14

Y1 - 2019/3/14

N2 - Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu 4 PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease.

AB - Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu 4 PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease.

KW - Parkinson's disease

KW - Positive allosteric modulator (PAM)

KW - VU2957

KW - metabotropic glutamate receptor 4 (mGlu )

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U2 - 10.1021/acsmedchemlett.8b00426

DO - 10.1021/acsmedchemlett.8b00426

M3 - Article

AN - SCOPUS:85055174677

VL - 10

SP - 255

EP - 260

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 3

ER -

Panarese JD, Engers DW, Wu YJ, Bronson JJ, Macor JE, Chun A et al. Discovery of VU2957 (Valiglurax): An mGlu ₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease. ACS Medicinal Chemistry Letters. 2019 Mar 14;10(3):255-260. https://doi.org/10.1021/acsmedchemlett.8b00426